From BRCA1 to polygenic risk scores - Mutations associated risks in breast cancer-related genes

There has been huge progress over the last 30 years in identifying the familial component of breast cancer. Summary: Currently around 20% is explained by the high-risk genes BRCA1 and BRCA2, a further 2% from other high penetrance genes and around 5% from the moderate risk genes ATM and CHEK2. In contrast the more than 300 low penetrance Single Nucleotide Polymorphisms (SNPs) now account for around 28% and are predicted to account for most of the remaining 45% yet to be found. Even for high-risk genes which confer a 40-90% risk of breast cancer these SNPs can substantially affect the level of breast cancer risk. Indeed, the strength of family history and hormonal and reproductive factors are very important in assessing risk even for a BRCA carrier. Risks of contralateral breast cancer are also affected by SNPs as well as the presence of high or moderate risk genes. Genetic testing using gene panels is now commonplace. Key-messages: There is need for a more parsimonious approach to panels only testing those genes with a definite 2-fold increased risk, and only testing the genes with challenging management implications, such as CDH1and TP53, where there is strong clinical indication to do so. Testing of SNPs alongside genes is likely to provide more accurate risk assessment.